Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD

Bradley W Richmond,Timothy S Blackwell,Jacob Schaff,Hubaida Fuseini,Matthew K Xin,Jessica B Blackburn,Samira Mansouri,Georgii Vasiukov,Sergey Gutor,Rui-Hong Du,Sergey Novitskiy,Dawn C Newcomb,Vasiliy V Polosukhin,Wei Han,Ana Serezani,Lei Jin

doi:10.1038/s41385-020-00344-9

Abstract

Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4+ or CD8+ T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4+ and CD8+ effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.

Highlights

The airways are continuously exposed to endogenous and inhaled microbes and noninfectious irritants
Loss of the Secretory immunoglobulin A (SIgA) immunobarrier causes adaptive immune activation To examine the relationship between localized SIgA deficiency and lymphocyte accumulation in chronic obstructive pulmonary disease (COPD) airways, we obtained lung sections from 12 patients undergoing transplantation for advanced COPD and 8 lifelong nonsmokers (NS) whose lungs were rejected for lung transplantation (Supplementary Table 1)
SIgA+ airways from COPD patients had more CD8+ and CD4+ T lymphocytes than lifelong nonsmokers, the highest numbers of cells were in SIgA- airways from patients with COPD suggesting loss of SIgA is associated with recruitment of T lymphocytes to small airways

Summary

Introduction

The airways are continuously exposed to endogenous and inhaled microbes and noninfectious irritants. To prevent these stimuli from damaging the lung directly or indirectly through activation of inflammatory responses, the respiratory epithelium continuously maintains a frontline defense barrier on the airway surface. Inhaled microorganisms and environmental microparticles are trapped by surface mucus, inactivated or destroyed by soluble enzymatic and antimicrobial factors, agglutinated by antigenspecific mucosal immunoglobulins, and cleared from the airway via the mucociliary escalator.[1,2] When environmental agents traverse the frontline defense barrier and stimulate host cells, innate and/or adaptive immune responses, which represent second and third lines of defense, are activated to ensure elimination of invaders. There, pIgR is proteolytically cleaved releasing dIgA and the extracellular portion of pIgR (the secretory component or SC) into the airway lumen to form SIgA

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Conclusion